3-Heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5 b]indole-1-acetamide derivatives, their preparation and their application in therapeutics

ABSTRACT

The invention discloses and claims therapeutic uses of compounds of general formula (I)  
                 
 
Wherein X, R 1 , R 2  and R 3  are as described herein. The invention further discloses processes for preparing them, and novel intermediates therefor.

This application is a continuation of U.S. application Ser. No.10/509,695, filed Sep. 30, 2004, now allowed, which was the NationalStage of International application No. PCT/FR03/01,027, filed Apr. 2,2003, both of which are incorporated herein by reference in theirentirety; which claims the benefit of priority of French PatentApplication No. 02/04,158, filed Apr. 3, 2002.

The invention relates to3-heteroaryl-3,5-dihydro-4-oxo-4H-pyridazino[4,5-b]indole-1-acetamidederivative compounds.

Already known are 3,5-dihydropyridazino[4,5-b]indole derivativecompounds, described in document WO-A-0044384, which have in vitroaffinity for peripheral benzodiazepine receptors (PBR or p sites). Therestill exists a need to find and to develop products which exhibit a goodin vivo activity. The invention responds to this aim by providing newcompounds which exhibit in vitro and in vivo affinity for peripheralbenzodiazepine receptors.

The invention first provides the compounds of the general formula (I)below.

The invention also provides processes for preparing compounds of generalformula (I).

The invention further provides compounds which can be used in particularas synthesis intermediates of compounds of general formula (I).

The invention additionally provides for uses of compounds of generalformula (I) particularly in medicinal products or in pharmaceuticalcompositions.

The compounds of the invention are of the general formula (I):

in which

-   X represents a hydrogen or halogen atom,-   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group,-   R₂ and R₃ each independently of one another represent a hydrogen    atom or a (C₁-C₄)alkyl group, or else R₂ and R₃, together with the    nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl,    morpholinyl or 4-(C₁-C₄)-alkylpiperazinyl group, and-   Het represents a heteroaromatic group of pyridinyl, quinolinyl,    isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl type which may    carry one or more halogen atoms and/or one or more (C₁-C₄)alkyl    and/or (C₁-C₄)alkoxy groups.

The compounds of the invention may exist in the form of bases oraddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, although the salts of other acids useful, for example, forpurifying or isolating compounds of formula (I) likewise form part ofthe invention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates; that is, in the form of associations or combinations with oneor more molecules of water or with a solvent. Such hydrates and solvateslikewise form part of the invention.

In the context of the present invention

-   a halogen atom represents a fluorine, chlorine, bromine or iodine;-   a (C₁-C₄)alkyl group represents a linear or branched, saturated    aliphatic group containing 1 to 4 carbon atoms. By way of example,    mention may be made of methyl, ethyl, propyl, isopropyl, butyl,    isobutyl and tert-butyl groups;-   a (C₁-C₄)alkoxy group represents an oxygen radical containing 1 to 4    carbon atoms which is substituted by an alkyl group as defined    above.

Among the compounds of formula (I) provided by the invention, preferredcompounds are the compounds for which

-   X represents a halogen atom; and/or-   R₁ represents a (C₁-C₄)alkyl; and/or-   R₂ and R₃, each independently of one another, represent a    (C₁-C₄)alkyl group, or else R₂ and R₃, together with the nitrogen    atom bearing them, form a pyrrolidinyl or 4-(C₁-C₄)alkylpiperazinyl    group; and/or-   Het represents a heteroaromatic group of pyridinyl type which may    carry one or more halogen atoms and/or one or more (C₁-C₄)alkyl    and/or (C₁-C₄)alkoxy groups.

Compounds for which X, R₁, R₂, R₃ and Het are all as defined above inthe subgroups of preferred compounds are particularly preferred, andmore specifically, among these, the compounds for which X represents achlorine atom, R₁ represents a methyl group.

Among the compounds of formula (I) provided by the invention, by way ofexample, compounds of the invention are the following:

-   1:    7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide-   2:    7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide    hydrochloride (1:1)-   3:    7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide    hydrochloride (1:1)-   4:    7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide-   5:    7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide-   6:    7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide    hydrochloride (1:1)-   7: 7-chloro-N,N,    5-trimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide    hydrochloride (1:1)-   8:    7-chloro-N,N,5-trimethyl-4-oxo-3-(6-methylpyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide-   9:    7-chloro-N,N-diethyl-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide-   10    4-methyl-1-[2-[7-chloro-5-methyl-3-(pyridin-3-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]acet-1-yl]piperazine    hydrochloride (1:1)-   11:    1-[2-[7-chloro-5-methyl-3-(pyridin-3-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]acet-1-yl]pyrrolidine-   12    1-[2-[7-chloro-5-methyl-3-(pyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]acet-1-yl]pyrrolidine    hydrochloride (1:1)

The compounds of general formula (I) can be prepared by processes whichare illustrated hereinbelow.

Throughout the remainder of the description the intermediate compounds(II), (III), (IV) and (V) are those shown in the scheme below.

A compound of general formula (II) in which X and R₁ are as definedabove and R′ represents a (C₁-C₄)alkyl group is treated with a3-chloro-3-oxopropanoate of general formula ClCOCH₂CO₂R″, in which R″represents a (C₁-C₄)alkyl group, in a solvent such as dichloroethane atambient temperature in the presence of a Lewis acid, titaniumtetrachloride for example, to give the diester of general formula (III).

The keto ester function of the diester of general formula (III) isconverted into keto amide to give the compound of general formula (IV)by the action of an amine of general formula HNR₂R₃, in which R₂ and R₃are as defined above, in the presence of a catalyst such as4-(dimethylamino)pyridine.

According to a first preparation pathway the compound of general formula(IV) is treated in a polar solvent in the presence of acid with aheteroarylhydrazine to give an amide of general formula (I).

According to a second preparation pathway the compound of generalformula (IV) is treated with hydrazine with heating in a solvent such astoluene in the presence of a catalytic amount of acid to give apyridazinoindole of general formula (V). Finally an N-arylation reactionis performed on the pyridazinoindole of general formula (V) in thepresence of a heteroaryl halide, or else of a heteroarylboronic acidderivative and a metal salt, such as a copper salt, leading to acompound of general formula (I).

The reactants employed above are available commercially or are describedin the literature, or else can be prepared by methods which aredescribed therein or which are known to the skilled worker.

More particularly the boronic acid derivatives bearing a heteroaromaticgroup may be prepared by methods analogous to those known in theliterature (Synth. Commun. 1996, 26, 3543 and WO9803484).

The preparation of the starting compounds of general formula (II) isdescribed in the document WO-A-0044751 in the case where X is a chlorineatom. In the case where X is a fluorine atom the compound of generalformula (II) is prepared analogously starting from methyl6-fluoroindole-2-carboxylate, which is described in the literature (J.Med. Chem. 2000, 43, 4701).

The invention also provides the compounds of general formula (III),

in which

-   X represents a hydrogen or halogen atom,-   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group,-   R′ and R″, each independently of one another, represent a    (C₁-C₄)alkyl group,-   which are useful as synthesis intermediates for preparing compounds    of general formula (I).

The invention additionally provides the compounds of general formula(IV),

in which

-   X represents a hydrogen or halogen atom,-   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group,-   R′ represents a (C₁-C₄)alkyl group,-   R₂ and R₃, each independently of one another, represent a hydrogen    atom or a (C₁-C₄)alkyl group, or else R₂ and R₃, together with the    nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl,    morpholinyl or 4-(C₁-C₄)alkylpiperazinyl group,-   which are useful as synthesis intermediates for preparing compounds    of general formula (I).

The invention further provides the compounds of general formula (V)

in which

-   X represents a hydrogen or halogen atom,-   R₁ represents a hydrogen atom or a (C₁-C₄) alkyl group,-   R₂ and R₃, each independently of one another, represent a hydrogen    atom or a (C₁-C₄)alkyl group, or else R₂ and R₃, together with the    nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl,    morpholinyl or 4-(C₁-C₄) alkylpiperazinyl group,-   which are useful as synthesis intermediates for preparing compounds    of general formula (I).

The examples about to follow illustrate the preparation of somecompounds of the invention. These examples are not limitative and onlyillustrate the invention. The numbers of the compounds exemplified tieup with those given in the table thereafter, which illustrates thechemical structures and the physical properties of some compounds inaccordance with the invention. The elemental microanalyses and the IRand NMR spectra confirm the structures of the compounds obtained.

EXAMPLE 1 Compound 17-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide

1.1. Methyl 6-fluoro-1-methyl-1H-indole-2-carboxylate

A 60% suspension of 7.9 g (197 mmol) of sodium hydride (washed withpetroleum ether beforehand) and 36.1 g (176 mmol) of methyl6-fluoro-1H-indole-2-carboxylate (containing 10 to 20% of ethyl6-fluoro-1H-indole-2-carboxylate) in 250 ml of N,N-dimethylformamide isstirred at ambient temperature for 2 h. Then 12 ml (193 mmol) ofiodomethane in 50 ml of N,N-dimethylformamide are added and the mixtureis stirred at ambient temperature for 12 h.

The contents are poured into an ice/water mixture. Dichloromethane isadded and the aqueous phase is neutralized with hydrochloric acid (1N).The organic phase is separated off, washed with water, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residueis purified by chromatography on a silica gel column in a mixture ofsolvents (cyclohexane/dichloromethane: 50/50 to 0/100 thendichloromethane/ethyl acetate: 100/0 to 70/30). 32.7 g (170 mmol) areisolated of a white compound of methyl6-fluoro-1-methyl-1H-indole-2-carboxylate containing 10 to 20% of ethyl6-fluoro-1-methyl-1H-indole-2-carboxylate.

1.2. methyl3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropanoate

In portions, 6.5 ml (60 mmol) of methyl 3-chloro-3-oxo-propanoate areadded to a solution of 6.6 ml (60 mmol) of titanium tetrachloride in 80ml of 1,2-dichloro-ethane. The mixture is stirred at ambient temperaturefor 30 minutes. A solution of 5 g (24.1 mmol) of methyl6-fluoro-1-methyl-1H-indole-2-carboxylate (containing 10 to 20% of ethyl6-fluoro-1-methyl-1H-indole-2-carboxylate), obtained in step 1.1., isadded and the mixture is stirred at 40° C. for 20 h. The mixture ispoured into ice water and extracted with dichloromethane. The organicphase is separated off, washed with water, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue ispurified by chromatography on a silica gel column (eluent:cyclohexane/dichloromethane: 90/10 to 0/100 then dichloromethane/ethylacetate 100/0 to 50/50). This gives 13 g of a pasty solid containingprimarily the compound. It is used as it is in the rest of thesynthesis.

1.3N,N-dimethyl-3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropanamide

A stream of gaseous dimethylamine is passed into a mixture of 13 g (44.4mmol) of methyl3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate,obtained in step 1.2., and 0.2 g (1.63 mmol) of4-(N,N-dimethyl)aminopyridine in 80 ml of toluene. Immediately acondenser, surmounted by a balloon flask, is fitted and the solution isstirred at 100° C. for 20 h. The mixture is cooled to ambienttemperature and concentrated under reduced pressure. 200 ml ofdichloromethane, water and hydrochloric acid (1N) are added. The organicphase is separated off, washed with water, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue ispurified by chromatography on a silica gel column (eluent:cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate100/0 to 0/100). 4.6 g (14 mmol) are isolated of a yellow solid, whichis used as it is in the rest of the synthesis.

1.47-fluoro-N,N,5-trimethyl-4-oxo-3-(pyrid-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide

A solution of 1.4 g (4.1 mmol) ofN,N-dimethyl-3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropanamide,obtained in step 1.3., in 40 ml of absolute ethanol is heated at refluxfor 22 h with a few drops of glacial acetic acid and 1.4 g (12.8 mmol)of 2-pyridylhydrazine.

The mixture is cooled and concentrated under reduced pressure. Water and200 ml of dichloromethane are added. Sodium hydroxide solution is addedto a pH>10. The organic phase is separated off, washed with water, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue is purified by chromatography on a silica gel column in amixture of solvents (dichloromethane/ethyl acetate: 100/0 to 0/100, thenethyl acetate/methanol: 100/0 to 90/10). The product obtained issubsequently chromatographed on a neutral alumina column in a mixture ofsolvents (dichloromethane/ethyl acetate: 100/0 to 0/100, then ethylacetate/methanol: 100/0 to 90/10). This gives a solid, which is rinsedwith diethyl ether.

0.25 g (0.66 mmol) of compound is isolated in the form of a white solid.

Melting point: 222-223° C.; M+H⁺: 380.

EXAMPLE 2 Compound 67-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamidehydrochloride

2.1 ethyl3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropanoate

A solution of 6.2 ml (48.4 mmol) of ethyl 3-chloro-3-oxopropanoate in 70ml of 1,2-dichloroethane is cooled to 0° C. In small portions 5.3 ml(48.3 mmol) of titanium tetrachloride are added and the mixture isstirred at 0° C. for 30 minutes. A solution of 4.3 g (19.2 mmol) ofmethyl 6-chloro-1-methyl-1H-indole-2-carboxylate in 35 ml of1,2-dichloroethane is added and the mixture is stirred at ambienttemperature for 12 h. It is poured into ice water and extracted withdichloromethane. The organic phase is separated off, washed with water,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue is purified by chromatography on a silica gelcolumn (eluent: cyclohexane/ethyl acetate: 90/10 to 80/20). This gives ayellow solid, which is triturated in heptane and then in diisopropylether.

2.84 g (8.4 mmol) of compound are recovered, in the form of acream-colored solid.

2.23-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-N,N-dimethyl-3-oxopropanamide

A stream of gaseous dimethylamine is passed into a mixture of 15 g (44.4mmol) of ethyl3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate,obtained in step 2.1., and 0.2 g (1.63 mmol) of4-(N,N-dimethyl)aminopyridine in 100 ml of toluene. Immediately acondenser, surmounted by a balloon flask, is fitted and the solution isstirred at 100° C. under low pressure for 20 h. The mixture is cooled toambient temperature and concentrated under reduced pressure and theresidue is chromatographed on a silica gel column (eluent:cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate:100/0 to 0/100). This gives 3.8 g of a yellow solid which isrecrystallized from a dichloromethane/ethyl acetate mixture.

1.8 g (5.3 mmol) are isolated of a yellow-white solid.

2.37-chloro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide

A solution of 1.7 g (5.2 mmol) of3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-N,N-dimethyl-3-oxopropanamide,obtained in step 2.2., in 150 ml of toluene is heated at 90° C. for 24 hin the presence of 1.8 ml (36.8 mmol) of hydrazine monohydrate and acatalytic amount of p-toluenesulfonic acid.

The mixture is cooled, an insoluble product is collected by filtrationand is washed with water and then with diisopropyl ether and dried underreduced pressure.

1.70 g (5.2 mmol) of compound are isolated, in the form of a whitesolid.

Melting point: >300° C.

2.47-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamidehydrochloride

0.2 g (0.63 mmol) of7-chloro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide,obtained in step 2.3., is dissolved in 15 ml of N-methylpyrrolidone. Atambient temperature and under an argon atmosphere 0.11 ml (1.4 mmol) ofpyridine, 0.19 ml (1.4 mmol) of triethylamine, 1 g of molecular sieve,0.24 g (1.3 mmol) of cupric acetate and 0.22 g (1.4 mmol) of2-(pyridin-3-yl)-1,3,2-dioxaborinane are introduced. After 24 h ofreaction the insoluble fractions are removed by filtration and thesolution is admixed with 0.11 ml (1.4 mmol) of pyridine, 0.19 ml (1.4mmol) or triethylamine, 1 g of molecular sieve, 0.24 g (1.3 mmol) ofcupric acetate and 0.22 g (1.4 mmol) of2-(pyridin-3-yl)-1,3,2-dioxaborinane. The reaction is stirred for afurther 24 h. The insoluble fractions are removed by filtration and thefiltrate is concentrated under reduced pressure to remove the solvent.Dichloromethane and water are added. The aqueous phase is extracted withdichloromethane. The organic phases are combined and washed with water.They are dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue is purified by chromatography on a silicagel column (eluent: dichloromethane, then ethyl acetate/methanol: 100/0to 80/20). A solid is obtained which is dissolved in adichloromethane/methanol mixture. Ethyl acetate is added and the mixtureis partly concentrated. A solid is isolated by filtration and isrecrystallized from a mixture of ethanol and dichloromethane. 110 mg of7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide(Compound 5) are recovered, in the form of a white solid.

Melting point: 255-256° C.

The hydrochloride is formed by dissolving the solid isolated above in amixture of methanol and dichloromethane and by adding a 5N solution ofhydrochloric acid in propan-2-ol. After recrystallization from ethanol,0.09 g (0.20 mmol) of compound is isolated, in the form of a whitesolid.

Melting point: 250-252° C.: M+H⁺: 396.

EXAMPLE 3 Compound 104-methyl-1-[2-[7-chloro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]acet-1-yl]piperazinehydrochloride (1:1)

3.1.[3-(6-chloro-2-methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropion-1-yl]-4-methylpiperazine

A solution of 2.84 g (8.4 mmol) of ethyl3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropanoate,obtained in step 2.1. of example 2, in 160 ml of toluene is heated atreflux for 12 h in the presence of 3.7 ml (34 mmol) ofN-methylpiperazine and 110 mg (0.9 mmol) of4-(N,N-dimethylamino)pyridine.

The mixture is cooled to ambient temperature. 100 ml of dichloromethane,80 ml of water and 10 ml of 20% aqueous ammonia are added. The organicphase is separated off, the aqueous phase is extracted withdichloromethane (2 times 100 ml) and the organic phases are combined.They are washed with water, dried over sodium sulfate, filtered andconcentrated under reduced pressure and the residue is purified bychromatography on a silica gel column (eluent:dichloro-methane/methanol: 100/0 to 90/10). This gives 1.68 g (4.3 mmol)of a yellow oil.

3.2.4-methyl-1-[2-[7-chloro-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]acet-1-yl]piperazine

A solution of 1.68 g (4.3 mmol) of[3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxopropion-1-yl]-4-methylpiperazine,obtained in step 3.1., in 80 ml of toluene is heated at 90° C. for 24 hin the presence of 1.7 ml (35 mmol) of hydrazine monohydrate and acatalytic amount of p-toluenesulfonic acid.

The mixture is cooled, and the insoluble fraction is collected byfiltration and washed with water and then with diisopropyl ether and isdried under reduced pressure.

1.43 g (3.8 mmol) of compound are isolated, in the form of a whitesolid.

Melting point: >300° C.

3.3.4-methyl-1-[2-[7-chloro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl)acet-1-yl]piperazinehydrochloride (1:1) 0.45 g (1.2 mmol) of4-methyl-1-[2-[7-chloro-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl)acet-1-yl]piperazine,obtained in step 3.2., is dissolved in 30 ml of N-methylpyrrolidone. Atambient temperature and under an argon atmosphere 0.2 ml (2.4 mmol) ofpyridine, 0.34 ml (2.4 mmol) of triethylamine, 0.30 g of molecularsieve, 0.44 g (2.4 mmol) of cupric acetate and 0.39 g (2.4 mmol) of2-(pyridin-3-yl)-1,3,2-dioxaborinane are introduced. After 24 h ofreaction the insoluble fractions are removed by filtration and 0.2 ml(2.4 mmol) of pyridine, 0.34 ml (2.4 mmol) or triethylamine, 0.30 g ofmolecular sieve, 0.44 g (2.4 mmol) of cupric acetate and 0.39 g (2.4mmol) of 2-(pyridin-3-yl)-1,3,2-dioxaborinane are added to the solution.The reaction is stirred for a further 24 h. The insoluble fractions areremoved by filtration and the filtrate is concentrated under reducedpressure to remove the solvent. Dichloromethane and water are added. Theaqueous phase is extracted with dichloromethane. The organic phases arecombined and washed with water. They are dried over sodium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography on a silica gel column (eluent: dichloromethane/methanol:100/0 to 90/10). A white solid is recovered, whose hydrochloride isformed by dissolving it in a mixture of propan-2-ol and methanol and byadding a 0.1 N solution of hydrochloric acid in propan-2-ol. Afterrecrystallization from a mixture of propan-2-ol and methanol, 0.34 g(0.70 mmol) of compound is isolated, in the form of a white solid.

Melting point: 287° C. (decomposition); M+H⁺: 451.

EXAMPLE 4 Compound 8

7-chloro-N,N,5-trimethyl-4-oxo-3-(6-methylpyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide0.4 g (1.25 mmol) of7-chloro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide,obtained in step 2.3. of example 2, is dissolved in 45 ml ofN-methylpyrrolidone. At ambient temperature and under an argonatmosphere, 0.2 ml (2.5 mmol) of pyridine, 0.35 ml (2.5 mmol) oftriethylamine, 0.40 g of molecular sieve, 0.45 g (2.5 mmol) of cupricacetate and 0.80 g (3.6 mmol) of4,4,5,5-tetramethyl-2-(6-methylpyridin-3-yl)-1,3,2-dioxaborolane areintroduced. After 24 h of reaction 0.2 ml (2.5 mmol) of pyridine, 0.35ml (2.5 mmol) of triethylamine, 0.40 g of molecular sieve, 0.45 g (2.5mmol) of cupric acetate and 0.80 g (3.6 mmol) of4,4,5,5-tetramethyl-2-(6-methylpyridin-3-yl)-1,3,2-dioxaborolane areadded to the solution. The reaction is stirred for a further 24 h. Theinsoluble fractions are removed by filtration and the filtrate isconcentrated under reduced pressure to remove the solvent.Dichloromethane and water are added. The aqueous phase is extracted withdichloromethane. The organic phases are combined and washed with water.They are dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue is purified by chromatography on a silicagel column (eluent: dichloromethane/methanol: 100/0 to 80/20). Thisgives a solid, which is recrystallized from an isopropanol/methanolmixture.

0.12 g (0.29 mmol) of compound is isolated, in the form of a whitesolid.

Melting point: 253-255° C.; M+H⁺: 410.

The table below illustrates the chemical structures and physicalproperties of some compounds of the invention.

In the “Salt” column of these tables, “HCl” denotes a hydrochloride, “−”denotes a compound in base form. The acid:base molar ratios areindicated opposite. The abbreviation dec. signifies that at thetemperature given the solid is in the state of decomposition. TABLE (I)

Compound X R₁ NR₂R₃ Het Salt m.p. (° C.) 1 F CH₃ N(CH₃)₂ pyridin-2-yl —222-223 2 F CH₃ N(CH₃)₂ pyridin-3-yl HCl 1:1 244-250 3 F CH₃ N(CH₃)₂pyridin-4-yl HCl 1:1 267-270 4 Cl CH₃ N(CH₃)₂ pyridin-2-yl — 183-184 5Cl CH₃ N(CH₃)₂ pyridin-3-yl — 255-256 6 Cl CH₃ N(CH₃)₂ pyridin-3-yl HCl1:1 250-252 7 Cl CH₃ N(CH₃)₂ pyridin-4-yl HCl 1:1 275-279 8 Cl CH₃N(CH₃)₂ 6-methyl- — 253-255 pyridin-3-yl 9 Cl CH₃ N(CH₂CH₃)₂pyridin-3-yl — 199-200 10 Cl CH₃

pyridin-3-yl HCl 1:1 287 (dec.) 11 Cl CH₃

pyridin-3-yl — 267-268 12 Cl CH₃

pyridin-4-yl HCl 1:1 248-251

The compounds of the invention formed the object of pharmacologicaltests which demonstrated their advantage as substances with therapeuticactivities.

The compounds of the invention also exhibit characteristics ofsolubility in water, which promote effective in vivo activity.

Study of [³H]Ro5-4864 binding to peripheral benzo-diazepine receptors(PBR or p sites).

The affinity of the compounds of the invention for PBR or p sites(peripheral-type binding sites on benzodiazepines) was determined.

The p site receptors can be labeled selectively in rat kidney membranesincubated in the presence of [³H]Ro5-4864. The compounds of theinvention formed the object of an in vitro study with respect to theiraffinity for these receptors.

The animals used are male Sprague-Dawley rats (Iffa Credo) weighing 180to 300 mg. Following decapitation, the kidney is removed and the tissueis homogenized at 4° C. using a Polytron™ homogenizer for 2 min at 6/10of the maximum speed in 35 volumes of 50 mM Na₂HPO₄ phosphate buffer ata pH adjusted to 7.5 with NaH₂PO₄. The membrane homogenate is filteredthrough gauze and diluted 10 times with the buffer.

[³H]Ro5-4864 (specific activity: 70-90 Ci/mmol; New England Nuclear) ata concentration of 0.5 nM is incubated in the presence of 100 μl ofmembrane homogenate in a final volume of 1 ml of buffer containing thetest compound.

After incubation at 0° C. for 3 h the membranes are recovered byfiltration on Whatman GF/B™ filters washed with 2 times 4.5 ml of cold(0° C.) incubation buffer. The amount of radioactivity retained by thefilter is measured by liquid scintigraphy.

For each concentration of compound studied, the percentage inhibition ofthe binding of [³H]Ro5-4864, and then the IC₅₀ concentration, theconcentration which inhibits 50% of the specific binding, aredetermined. The IC₅₀ values of the best compounds of the invention rangefrom 1 nM to 200 nM.

The compounds of the invention are therefore ligands with affinity forperipheral benzodiazepine receptors.

Study of neurotropic activity.

Tests of survival of motor neurons following section of the facial nervein 4-day-old rats

After lesion of the facial nerve in the immature rat, the motor neuronsof the facial nucleus suffer neuronal death by apoptosis. Neuronalsurvival is evaluated by means of histological and neuronal countingmethods. Immature rats 4 days old are anesthetized with pentobarbital (3mg/kg i.p.). The right facial nerve is exposed and sectioned, at itsoutlet from the stylomastoid foramen. After waking, the young rats arereturned to their mother and treated for 7 days, with one or twoadministrations daily, orally or intraperitoneally, at doses rangingfrom 1 to 10 mg/kg. 7 days after the lesion, the animals are decapitatedand the brains are frozen in isopentane at −40° C. The facial nucleus iscut with a cryostat into 10 μm sections, in its entirety. The motorneurons are stained with cresyl violet and counted using the Histo™software (Biocom™).

In this model the compounds of the invention increased neuronal survivalby approximately 10 to 30%.

The results of the tests show that compounds of the invention promotenerve regeneration.

The compounds according to the invention can therefore be used forpreparing medicinal products.

Thus according to another of its aspects the invention providesmedicinal products which comprise a compound of formula (I) or anaddition salt thereof with a pharmaceutically acceptable acid or else ahydrate or a solvate of the compound of formula (I).

These medicinal products find their application in therapeutics,particularly for the prevention and/or treatment of peripheralneuropathies of various types, such as traumatic or ischemicneuropathies, infectious, alcoholic, medicinal or genetic neuropathies,and motor neuron conditions, such as spinal amyotrophies and amyotrophiclateral sclerosis. These medicinal products will also find applicationin the treatment of neurodegenerative diseases of the central nervoussystem, either of acute type, such as cerebral vascular accidents andcranial and medullar traumas, or of chronic type, such as autoimmunediseases (multiple sclerosis), Alzheimer's disease, Parkinson's diseaseand any other disease in which the administration of neurotrophicfactors is supposed to have a therapeutic effect.

The compounds according to the invention can also be used in thetreatment of acute or chronic renal insufficiency, glomerulonephritis,diabetic nephropathy, cardiac ischemia and cardiac insufficiency,myocardial infarction, ischemia of the lower limbs, coronary vasospasm,angina pectoris, pathologies associated with the heart valves,inflammatory heart diseases, side effects due to cardiotoxic medicamentsor following cardiac surgery, atherosclerosis and its thromboemboliccomplications, restenosis, graft rejections, or ailments linked toincorrect proliferation or incorrect migration of the smooth musclecells.

Furthermore, recent data in the literature indicate that the peripheralbenzodiazepine receptor might play a fundamental part in the regulationof cell proliferation and cancerization processes. Generally, and incomparison with normal tissues, an increased density of peripheralbenzodiazepine receptors is observed in various types of tumors andcancers.

In human astocytomas the degree of expression of the peripheralbenzodiazepine receptor is correlated with the degree of malignancy ofthe tumor, the proliferation index and the survival of the patients. Inhuman cerebral tumors the increase in the number of peripheralbenzodiazepine receptors is used as a diagnostic indication in medicalimaging and as a therapeutic target for conjugates formed from a ligandof the peripheral benzodiazepine receptor and a cytostatic drug. A highdensity of peripheral benzodiazepine receptors is also observed inovarian carcinomas and breast cancers. As regards the latter, it hasbeen demonstrated that the degree of expression of the peripheralbenzodiazepine receptors is related to the aggression potential of thetumor; moreover, the presence of a peripheral benzodiazepine receptoragonist stimulates the growth of a mammary cancer line.

The entirety of these results, which suggests a deleterious function ofthe peripheral benzodiazepine receptor in cancerization processes,constitutes a relevant basis for the search for synthetic ligandsspecific to the peripheral benzodiazepine receptor which are capable ofblocking its effects.

The compounds can therefore be used for treating tumors and cancers.

Peripheral benzodiazepine receptors are also present in the skin and, inthis respect, the compounds which can be used according to the inventioncan be used for the prophylaxis or treatment of cutaneous stresses.

By cutaneous stresses are meant the various situations which could causedamage, in particular to the epidermis, irrespective of the agentcausing this stress. That agent may be internal and/or external to thebody, such as a chemical or free-radical agent, or else external, suchas ultraviolet radiation. Accordingly the compounds which can be usedaccording to the invention are intended for preventing and combatingskin irritation, dry patches, erythemas, disesthesic sensations, heatingsensations, pruritus of the skin and/or of the mucosae, or ageing, andcan also be used in skin disorders such as, for example, psoriasis,pruriginous diseases, herpes, photodermatoses, atopic dermatites,contact dermatites, lichens, prurigos, insect stings, in fibroses andother collagen maturation disorders, in immunological disorders or elsein dermatological conditions, such as eczema.

The compounds of the invention can also be used for preventing andtreating chronic inflammatory diseases, especially rheumatoid arthritis.

According to another of its aspects the invention providespharmaceutical compositions comprising as active principle at least onecompound of general formula (I). These pharmaceutical compositionscomprise an effective dose of at least one compound of the invention, inthe form of the base, a pharmaceutically acceptable salt, a solvate or ahydrate, and optionally in combination with at least onepharmaceutically acceptable excipient. Said excipients are selectedaccording to the pharmaceutical form and the desired method ofadministration from among the customary excipients, which are known tothe skilled worker.

In the pharmaceutical compositions of the invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal, rectal, or intraocularadministration, the active principle of general formula (I) above, orits salt, solvate or hydrate where appropriate, may be administered inunit administration form, as a mixture with at least one conventionalpharmaceutical excipient, to animals and to human beings for theprophylaxis or treatment of the above disorders and diseases.

The unit administration forms may be, for example, tablets, gelcapsules, granules, powders, oral or injectable solutions orsuspensions, transdermal patches, forms for administration sublingually,buccally, intratracheally, intraocularly, intranasally or by inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms or implants. Fortopical administration consideration may be given to creams, gels,ointments, lotions or eyewashes.

These pharmaceutical forms are prepared in accordance with the methodsthat are customary in the fields in question.

Said unit forms are dosed so as to allow daily administration of from0.001 to 20 mg of active principle per kg of body weight, depending onthe pharmaceutical form.

There may be specific cases in which higher or lower doses areappropriate; such dosages are not outside the scope of the invention. Inaccordance with common practice, the dosage appropriate to each patientis determined by the clinician in accordance with the method ofadministration, the weight and the response of said patient.

The present invention according to another of its aspects also providesa method of treating the pathologies indicated above which comprisesadministering to a patient an effective dose of a compound according tothe invention or one of its pharmaceutically acceptable salts orhydrates or solvates.

1. A compound of the formula (III):

in which X represents a hydrogen or halogen atom, R₁ represents ahydrogen atom or a (C₁-C₄)alkyl group, R′ and R″, each independently ofone another, represent a (C₁-C₄)alkyl group.
 2. A compound of theformula (IV):

in which X represents a hydrogen or halogen atom, R₁ represents ahydrogen atom or a (C₁-C₄)alkyl group, R′ represents a (C₁-C₄)alkylgroup, R₂ and R₃, each independently of one another, represent ahydrogen atom or a (C₁-C₄)alkyl group, or else R₂ and R₃, together withthe nitrogen atom bearing them, form a pyrrolidinyl, piperidinyl,morpholinyl or 4-(C₁-C₄)alkylpiperazinyl group.
 3. A method of treatinga disease in a patient, said disease selected from the group consistingof peripheral neuropathy, Alzheimer's disease and Parkinson's disease,comprising administering to said patient an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof:

in which X represents a hydrogen or halogen atom, R₁ represents ahydrogen atom or a (C₁-C₄)alkyl group, R₂ and R₃ each independently ofone another represent a hydrogen atom or a (C₁-C₄)alkyl group, or elseR₂ and R₃, together with the nitrogen atom bearing them, form apyrrolidinyl, piperidinyl, morpholinyl or 4-(C₁-C₄)alkylpiperazinylgroup, and Het represents a heteroaromatic group of pyridinyl,quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl typewhich may carry one or more halogen atoms and/or one or more(C₁-C₄)alkyl and/or (C₁-C₄)alkoxy groups.
 4. The method according toclaim 3, wherein X represents a halogen atom.
 5. The method according toclaim 3, wherein R₁ represents a (C₁-C₄)alkyl.
 6. The method accordingto claim 3, wherein R₂ and R₃, each independently of one another,represent a (C₁-C₄)alkyl group or else R₂ and R₃, together with thenitrogen atom bearing them, form a pyrrolidinyl or4-(C₁-C₄)alkylpiperazinyl group.
 7. The method according to claim 3,wherein Het represents a heteroaromatic group of pyridinyl type whichmay carry one or more halogen atoms and/or one or more (C₁-C₄)alkyland/or (C₁-C₄)alkoxy groups.
 8. The method according to claim 3, whereinX represents a chlorine atom and R₁ represents a methyl group.
 9. Themethod according to claim 3, wherein the disease is peripheralneuropathy.
 10. The method according to claim 3, wherein the disease isAlzheimer's disease.
 11. The method according to claim 3, wherein thedisease is Parkinson's disease.
 12. The method according to claim 4,wherein the disease is peripheral neuropathy.
 13. The method accordingto claim 4, wherein the disease is Alzheimer's disease.
 14. The methodaccording to claim 4, wherein the disease is Parkinson's disease. 15.The method according to claim 5, wherein the disease is peripheralneuropathy.
 16. The method according to claim 5, wherein the disease isAlzheimer's disease.
 17. The method according to claim 5, wherein thedisease is Parkinson's disease.
 18. The method according to claim 6,wherein the disease is peripheral neuropathy.
 19. The method accordingto claim 6, wherein the disease is Alzheimer's disease.
 20. The methodaccording to claim 6, wherein the disease is Parkinson's disease. 21.The method according to claim 7, wherein the disease is peripheralneuropathy.
 22. The method according to claim 7, wherein the disease isAlzheimer's disease.
 23. The method according to claim 7, wherein thedisease is Parkinson's disease.
 24. The method according to claim 8,wherein the disease is peripheral neuropathy.
 25. The method accordingto claim 8, wherein the disease is Alzheimer's disease.
 26. The methodaccording to claim 8, wherein the disease is Parkinson's disease.